It is still not clear why some children have life-threatening RSV disease. Molecular diagnostics enable sensitive detection of respiratory viruses but their clinical significance remains unclear in pediatric lower respiratory tract infections (LRTI). We aimed to determine whether viral coinfections increase life-threatening disease in a large cohort. As part of the Severe Acute Respiratory Illness (SARI) hospitalization sentinal surveillance conducted in South Africa from February 2009-December 2013, molecular testing for respiratory viruses was performed in 2.322 HIV-uninfected children with RSV-associated LRTI. We found that RSV and any viral coinfection compared to RSV monoinfection is not associated with more severe disease (OR:0.74, 95%CI 0.39-1.4). However, increased life-threatening disease in RSV-adenovirus (aOR: 3.4, 95%CI: 1.6-7.2, p=0.001)and RSV-Influenza coinfection (aOR: 2.1, 95%CI 1.0-4.5, p=0.05) warrants further study.​